title: Pharmacological enhancement of δ-subunit-containing GABA(A) receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice.
abstract: The development of new strategies for the treatment of acute pain requires the identification of novel nonopioid receptor targets. This study explored whether δ-subunit-containing GABA(A)Rs (δGABA(A)Rs) in neurons of the spinal cord dorsal horn generate a tonic inhibitory conductance in vitro and whether δGABA(A)R activity regulates acute nociception. Whole-cell recordings revealed that δGABA(A)Rs generate a tonic inhibitory conductance in cultured spinal neurons and lamina II neurons in spinal cord slices. Increasing δGABA(A)R function by applying the δGABA(A)R-preferring agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP) increased the tonic current and inhibited neuronal excitability in spinal neurons from wild-type (WT) but not δ subunit null-mutant (Gabrd(-/-)) mice. In behavioral studies, baseline δGABA(A)R activity did not regulate acute nociception; however, THIP administered intraperitoneally or intrathecally attenuated acute nociception in WT but not Gabrd(-/-) mice. In the formalin nociception assay, the phase 1 response was similar for WT and Gabrd(-/-) mice. In contrast, the phase 2 response, which models central sensitization, was greater in Gabrd(-/-) mice than WT. THIP administered intraperitoneally or intrathecally inhibited phase 1 responses of WT but not Gabrd(-/-) mice and had no effect on phase 2 responses of WT mice. Surprisingly, THIP reduced the enhanced phase 2 response in Gabrd(-/-) mice. Together, these results suggest that δGABA(A)Rs in spinal neurons play a major physiological and pharmacological role in the regulation of acute nociception and central sensitization. Spinal δ-subunit-containing GABA(A) receptors were identified with electrophysiological methods and behavioral models as novel targets for the treatment of acute pain.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 Unité de neurosciences cellulaires et moléculaires, Centre de Recherche Université Laval Robert-Giffard, Quebec, Canada G1J 2G3 Department of Psychiatry & Neuroscience, Université Laval, Quebec, Canada G1J 2G3 Departments of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8 Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada M5S 1A8 Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Bonin
authors.forename: Charalampos
authors.initials: C
authors.lastname: Labrakakis
authors.forename: David G
authors.initials: DG
authors.lastname: Eng
authors.forename: Paul D
authors.initials: PD
authors.lastname: Whissell
authors.forename: Yves
authors.initials: Y
authors.lastname: De Koninck
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000700:Analgesics / Q000494:pharmacology*; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005557:Formaldehyde / Q000009:adverse effects; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D019417:Hindlimb Suspension / Q000379:methods; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects; D011963:Receptors, GABA-A / Q000172:deficiency / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000777:Anesthetics; D058787:GABA-A Receptor Antagonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D005557:Formaldehyde; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol; D001640:Bicuculline